EP3641738A1 - Produits hémostatiques - Google Patents

Produits hémostatiques

Info

Publication number
EP3641738A1
EP3641738A1 EP18819809.7A EP18819809A EP3641738A1 EP 3641738 A1 EP3641738 A1 EP 3641738A1 EP 18819809 A EP18819809 A EP 18819809A EP 3641738 A1 EP3641738 A1 EP 3641738A1
Authority
EP
European Patent Office
Prior art keywords
hemostatic
nozzle
hemostatic product
product
polymeric material
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18819809.7A
Other languages
German (de)
English (en)
Other versions
EP3641738A4 (fr
Inventor
Timothy Floyd
Philip A. Messina
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
St Teresa Medical Inc
Original Assignee
St Teresa Medical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by St Teresa Medical Inc filed Critical St Teresa Medical Inc
Publication of EP3641738A1 publication Critical patent/EP3641738A1/fr
Publication of EP3641738A4 publication Critical patent/EP3641738A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/38—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the invention relates to products having hemostatic characteristics. More particularly, the invention relates to products having encapsulated hemostatic components.
  • the body's natural response to stem bleeding from a wound is to initiate blood clotting via a complex process known as the coagulation cascade.
  • the cascade involves two pathways that ultimately lead to the production of the enzyme thrombin, which catalyzes the conversion of fibrinogen to fibrin.
  • Fibrin is then cross-linked to form a clot, resulting in hemostasis.
  • the body is usually able to carry out this process efficiently in a manner that prevents excessive loss of blood from the wound.
  • this may not be the case.
  • Biomaterials, p. 50-57 (2006) discloses electrospun fibers that are a composite of poly(c- caprolactone) as a shell and dextran as a core. These fibers provide the slow release of agents (bovine serum albumin, BSA) that are also electrospun into the fibers.
  • agents bovine serum albumin, BSA
  • MacPhee et al. U.S. Pat. No. 6,762,336, teaches a hemostatic multilayer bandage that comprises a thrombin layer between two fibrinogen layers.
  • the bandage may contain other resorbable materials such as glycolic acid or lactic acid based polymers or copolymers. Neither electrospun fibers nor dextran fibers are taught as components of the bandage.
  • compositions comprise a cellulose containing article (e.g. gauze) to which a polysaccharide is covalently or ionically crosslinked.
  • the crosslinked polysaccharide may be dextran.
  • the compositions are not electrospun and exogenous clotting agents are not included in the compositions.
  • Wnek et al. U.S. Patent Publication No. 2004/0018226, discloses fibers produced by an electroprocessing technique such as electrospinning.
  • the fibers comprise enclosures within the fibers for containing substances that are not miscible with the fibers. Dextran is not taught as a fiber component.
  • wound dressing comprised of various biodegradable polymers and hydrogels having allogenic or autologous precursor cells (e.g. stem cells) dispersed within the polymers.
  • the polymers may be prepared by electrospinning, and one polymer component may be dextran.
  • the polymers cannot be immediately soluble upon contact with liquid, as they must provide a scaffolding for delivery of the cells over time, even though the polymers eventually biodegrade in situ.
  • Li et al. U.S. Patent Publication No. 2008/0265469, describes electrospun nanofibers that may include dextran. However, the nanofibers are not described as readily soluble in liquids.
  • Eskridge et al. U.S. Patent Publication No. 2009/0053288, teaches a woven hemostatic fabric comprised of about 65% fiberglass yarn and about 35% bamboo yarn.
  • the fiberglass component may be electrospun, and hemostatic factors such as thrombin may be associated with the fabric, e.g. by soaking the material in a solution of thrombin.
  • dextran may be added as a hygroscopic agent.
  • Bowlin et al. U.S. Patent Publication No. 2011/0150973, discloses a method of delivering one or more agents of interest to a location of interest.
  • the method includes applying or delivering to a location of interest a hemostatic product.
  • the hemostatic product includes electrospun dextran fibers that dissolve upon contact with liquid.
  • the hemostatic product also includes one or more agents of interest associated with said electrospun dextran fibers. Applying or delivering results in dissolution of the electrospun dextran fibers in liquid at the location of interest to thereby release the one or more agents of interest into the liquid.
  • An embodiment of the invention is directed to a method of forming a hemostatic product.
  • a solution is formed with a polymeric material.
  • An electrospinning system is provided having a first nozzle and a second nozzle. The polymeric material solution passes through the first nozzle and a hemostatic agent passes through the second nozzle to form an electrospun fiber in which the polymeric material at least partially covers the hemostatic agent. The electrospun fiber is deposited on a support to form the hemostatic product.
  • Another embodiment is directed to a hemostatic product that includes an electrospun fiber.
  • a polymeric material at least partially covers a hemostatic agent core.
  • Another embodiment of the invention is directed to method of forming a hemostatic product.
  • a solution is formed with a polymeric material.
  • a first electrospinning system is provided having a first nozzle and a second nozzle.
  • the polymeric material solution is passed through the first nozzle on the first electrospinning system and a first hemostatic agent is passed through the second nozzle on the first electrospinning system to form a first electrospun fiber in which the polymeric material at least partially covers the first hemostatic agent.
  • a second electrospinning system is provided having a first nozzle and a second nozzle.
  • the polymeric material solution passes through the first nozzle on the second electrospinning system and a second hemostatic agent passes through the second nozzle on the second electrospinning system to form a second electrospun fiber in which the polymeric material at least partially covers the second hemostatic agent.
  • the first hemostatic agent is different than the second hemostatic agent.
  • the first electrospun fiber and the second electrospun fiber are deposited on a support to form the hemostatic product.
  • FIG. 1 is a schematic view of an electrospinning apparatus according to an embodiment of the invention.
  • FIG. 2 is a side view of an electrospinning nozzle for the electrospinning apparatus.
  • Fig. 3 is an end view of the electrospinning nozzle.
  • Fig. 4 is an end view of another embodiment of the electrospinning nozzle.
  • An embodiment of the invention is directed to a system for providing hemostasis in a person or animal.
  • the system generally includes a hemostatic product that contains at least one hemostatic agent.
  • the hemostatic agent is encapsulated within the hemostatic product to reduce the potential of the hemostatic agent from becoming disassociated from the hemostatic product. Encapsulating the hemostatic agent also enhances the stability of the hemostatic product such that it is possible for the hemostatic product to be stored for an extended period of time prior to use without the hemostatic product experiencing degradation.
  • the materials used to fabricate the hemostatic product dissolve to thereby release the active agents to the injury site and provide the hemostatic effect.
  • the hemostatic product may be used in trauma situations where the condition of the patient must be stabilized until it is possible to transport the patient to a treatment facility having medical treatment equipment that is more advanced to the medical treatment equipment available where the patient was injured.
  • the hemostatic product only dextran and the hemostatic agents are used in the hemostatic product and thus after clot formation, there is no need to disturb the clot to remove hemostatic product components, since none remain at the site.
  • the hemostatic product thereby does not leave any residual foreign bodies that elicit foreign body reactions or act as a nidus for infection.
  • the hemostatic product does not contain any xenoproteins, which have the potential of eliciting immune reactions in persons on which the hemostatic product is used.
  • the components used in fabricating the hemostatic product should be selected to be the same as components found in a living body where the hemostatic product is to be used. Alternatively, the components used in fabricating the hemostatic product are compatible with and readily broken down when the hemostatic product is used on or in a living body. [0034] Using such a process minimizes complications associated with components of the hemostatic product not being promptly being broken down as such a process could cause inflammation in the living body. The only thing that remains after the use of the hemostatic product is the clot, which most living bodies are adapted to degrade over time.
  • the hemostatic system generally includes a hemostatic product having a sheet that is fabricated from electrospun fibers in which the at least one hemostatic agent is encapsulated.
  • Electrospinning is a non-mechanical processing strategy and can be scaled to accommodate the large volumes necessary to meet the needs of commercial processing. Additional details on the electrospinning process are provided in U.S. Application Ser. No. 12/937,322, the contents of which are incorporated herein by reference.
  • FIG. 1 A schematic illustration of an electrospinning system used in conjunction with the electrospinning process is set forth in Fig. 1.
  • Fig. 1 A significant difference between this electrospinning system and the electrospinning system described in the application referenced above is that this system utilizes a multi-nozzle configuration.
  • the multi -nozzle 10 includes a first nozzle 20 and a second nozzle 22.
  • the first nozzle 20 extends at least partially around the second nozzle 22 as illustrated in Figs. 2 and 3.
  • the first nozzle 20 extends substantially around the second nozzle 22 as illustrated in Fig. 3. This configuration facilitates encapsulating the material fed through the second nozzle 22 with the material that is fed through the first nozzle 20.
  • the hemostatic agent may be fed through the second nozzle 22.
  • the hemostatic agent is provided in a powder form that is propelled through the second nozzle 22 such as with a gas.
  • the hemostatic agent includes thrombin and fibrinogen
  • the thrombin and fibrinogen may be mixed together before the hemostatic agent is fed through the second nozzle 22.
  • the thrombin may be fed through a second nozzle 122 and the fibrinogen may be fed through a third nozzle 124 that are separate from each other but both located within the first nozzle 120 of the multi-nozzle device 110.
  • Such a configuration may facilitate changing the rates at which the different hemostatic agents are added to the electrospun fibers. This configuration may also reduce the potential of interactions between the hemostatic agents prior to the hemostatic agents being incorporated into the electrospun fibers.
  • the concepts of the invention may also be expanded to use more than 3 nozzles when forming the electrospun fibers depending on the number of materials used in fabricating the electrospun fibers and the associated incompatibilities or desire to vary the rate at which the material is delivered.
  • the hemostatic agents may be separately incorporated into the electrospun fibers using a separate electrospinning system for each of the hemostatic agents.
  • a separate electrospinning system may be used with the individual hemostatic agents at separate times. In either of these situations, when forming the hemostatic product, layers having the different hemostatic agents will be placed in a stacked configuration.
  • the material fed through the first nozzle 20 is substantially dextran.
  • substantially dextran means that greater than about 90 percent of the material fed through the first nozzle 20 is dextran other than the solvent in which the dextran is dissolved. In other embodiments, the material fed through the first nozzle 20 is only dextran other than the solvent in which the dextran is dissolved.
  • the amount of dextran used in each hemostatic product can vary depending on the size of hemostatic product that is being manufactured, with typical hemostatic product formulations using from about 5-10 grams of dextran (usually 100,000-200,000 Mr) per hemostatic product.
  • a solution of dextran for electrospinning will be of a concentration in the range of between about 0.1 and about 10 grams per milliliters of solvent.
  • the dextran concentration is between about 0.5 and about 5 grams per milliliter, and usually such a solution is at a concentration of about 1 gram per milliliter, which is about 0.15 milligrams.
  • a preferred range would be from about 0.9 to about 1.1 grams of dextran per milliliter of solution that is to be electrospun.
  • the concentration of the dextran in the dextran and water solution is between about 40 percent by weight and about 60 percent by weight. In other embodiments, the concentration of the dextran is between about 45 percent by weight and about 55 percent by weight.
  • a diameter of the electrospun fibers may be affected such as by changing the rate at which the dextran solution is provided to the electrospinning machine.
  • the electrospun fibers have a diameter of between about 3 micrometers and about 4 micrometers.
  • the area (length and width) of the hemostatic product of the invention can vary and be adjusted by adjusting spinning parameters.
  • the mats of dextran fibers can be cut to a desired size after spinning.
  • the hemostatic product will be from about 0.5 centimeters or less to about 30 centimeters or more in length and/or width, but larger or smaller sizes are also contemplated depending on the intended use of the hemostatic system.
  • the agents are bioactive agents that have a beneficial or therapeutic effect at the wound site.
  • the site is a bleeding wound at which it is desired to form a blood clot to stop or slow the bleeding.
  • the therapeutic substances of interest may include, for example, thrombin and fibrinogen, although other agents active in promoting hemostasis, including but not limited to capscian, may also be included.
  • the thrombin and/or fibrinogen that are used in the hemostatic product are in forms that are biologically active when they come into contact with blood. Hence upon dissolution, the thrombin acts on the fibrinogen, converting it to fibrin, which then forms a clot within the wound to thereby staunch the flow of blood.
  • the thrombin and fibrinogen may be derived from human sources.
  • the thrombin and fibrinogen are salmon thrombin and fibrinogen.
  • Advantages of using salmon as a source of these materials include but are not limited to the lack of concern about transmission of etiologic agents (e.g. viruses) that may occur when human and other mammalian sources of thrombin or fibrinogen (e.g. bovine) are used.
  • the hemostatic agent is fed through the second nozzle 22 at a rate that is sufficient to provide the electrospun fibers with an effective concentration of the hemostatic agent for achieving hemostasis when the hemostatic product is applied to a wound.
  • the effective concentration thereby depends on factors such as the amount of electrospun fibers that are used in the hemostatic product and the anticipated rate of blood flow that is intended to be stopped through the use of the hemostatic product.
  • the quantity of fibrinogen used in the hemostatic product may be adjusted by changing either the concentration of the fibrinogen in the hemostatic mixture or changing the rate at which the hemostatic mixture is used in the hemostatic product.
  • the quantity of fibrinogen added to the hemostatic product is generally in the range of from about 10 milligrams to about 3 grams. In certain embodiments, the amount of fibrinogen in each of the hemostatic products is between about 20 milligrams to about 1 gram.
  • the quantity of thrombin used in the hemostatic product may be adjusted by changing either the concentration of the thrombin in the hemostatic mixture or changing the rate at which the hemostatic mixture is used in the hemostatic product.
  • the quantity of thrombin added to each of the hemostatic products is generally between about 10 and 10,000 N H Units. In certain embodiments, the amount of thrombin in each of the hemostatic products is between about 20 and 6,000 NIH Units.
  • active agents may also be associated with the electrospun dextran base using a variety of techniques that are known to those of skill in the art, and will depend in part on the precise form of the substance and the means at hand. For example, for powdered, particulate thrombin and fibrinogen, association may be carried out by sprinkling, shaking, blowing, etc. the agents onto a layer of the excipient or carrier.
  • active agents such as thrombin may be electrosprayed with sucrose to form sugar droplets, which tends to stabilize thrombin and can also "trap" other substances of interest for delivery to the hemostatic product.
  • the therapeutic agents may themselves be electrospun.
  • the therapeutic agents are dissolved in and electrospun from a solution.
  • the active agents may be electrospun into other forms such as droplets, beads, etc.
  • electrospun or non-electrospun collagen agents that absorb water, various dry salts that would tend to absorb fluids when placed in contact with e.g. blood; engineered thrombin or thrombin mimics; engineered fibrinogen; agents that cause vasospasm (e.g. ADP, 5-hydroxytryptamine, 5-HT and thromboxane, (TXA-2) to help contract and seal a bleeding vessel, etc. may also be included.
  • vasospasm e.g. ADP, 5-hydroxytryptamine, 5-HT and thromboxane, (TXA-2) to help contract and seal a bleeding vessel, etc.
  • tissue factors that are normally only expressed on the surface of damaged cells and that start the normal clotting cascade
  • serotonin which enhances platelet clumping and promotes vessel constriction
  • other agents that are used to replace missing components of the clotting cascade in hemophilia, for example, factor 7 (which activates the so called external extrinsic coagulation cascade) and crude extracts of platelets.
  • Active agents that function to promote late stages of wound healing may also be included to, for example, facilitate cell migration and remodeling.
  • the incorporation of collagen is an example of such an active agent.
  • the therapeutic agents must be amenable to drying and are associated with the other components of the hemostatic product in the dry state, since liquid may negatively affect at least one of the components used in the hemostatic product.
  • the active agents may be desiccated or lyophilized, or water may be removed by other means.
  • the material is electrospun onto a vacuum table to retain the electrospun material in a substantially stationary position during the fabrication process. Retaining the electrospun material in the substantially stationary position enhances the ability to fabricate the hemostatic product such as placing components on the electrospun material and accurately cutting the electrospun material into the hemostatic product.
  • the hemostatic product prefferably be formed in more than one layer.
  • a hemostatic product may contain 1-2 layers. In other embodiments the hemostatic product may include between 2-20 layers.
  • the height or thickness of the hemostatic product can vary considerably depending on the intended use of the hemostatic product.
  • the hemostatic product has a thickness of between about 0.1 millimeter and about 5 centimeters. In other embodiments, the thickness of the hemostatic product is between about 0.3 millimeters and about 0.50 millimeters.
  • the thickness of the hemostatic product may impact the rate of dissolution of the dextran upon contact with liquid. For example, a thin hemostatic product (e.g. about 2 millimeters) will dissolve more rapidly than a hemostatic product that is thicker, providing the loft of the fibers is comparable.
  • dissolution of the dextran fibers is extremely rapid, e.g. about 5 minutes or less after exposure to liquid, or about 4 minutes or less, or about 3 minutes or less, or about 2 minutes or less, or about 1 minute or less.
  • the hemostatic product substantially dissolves in between about 1 second and about 20 seconds. As used herein, “substantially dissolves” means that less than about 20 percent of the electrospun fibers remain in fiber form. In other embodiments, “substantially dissolves” means that less than about 10 percent of the electrospun fibers remain in fiber form.
  • immediate dissolution Compression of an electrospun dextran mat may be used to modulate the rate of dissolution, with greater levels of compression inversely impacting the rate, i.e. generally, the greater the degree of compression, the slower the rate of dissolution.
  • the rapid rate of dissolution is advantageous, particularly when delivering biologically active agents (e.g. hemostatic agents) to a site of action such as a wound. Rapid dissolution of the carrier dextran fibers provides extremely rapid delivery of the hemostatic agents to the wound upon deployment of the hemostatic product.
  • biologically active agents e.g. hemostatic agents
  • thrombin is included in the hemostatic product, it may be desirable to reduce the moisture content of the hemostatic product (e.g. a bandage or gauze) to less than about 5% to preserve thrombin activity during sterilization.
  • This moisture content reduction can be achieved by drying the fabricated hemostatic product, e.g., under a vacuum, or by using a fabrication method that reduces moisture content from the beginning.
  • the hemostatic product should be protected from exposure to moisture because when the components used in the hemostatic product are exposed to moisture, the components degrade such as by dissolving.
  • the hemostatic product may include one or more stabilizers such as is described in U.S. application Ser. No. 13/622,690, which is assigned to the assignee of the present application and the contents of which are incorporated herein by reference.
  • the stabilizers may enhance the ability of the hemostatic product to dissolve when the hemostatic products are applied to the injury site.
  • the hemostatic product Prior to use of the hemostatic product, it may be desirable for the hemostatic product to be carried by a person on whom the hemostatic product could potentially be used and/or by a person who could potentially use the hemostatic product. In other embodiments, the hemostatic product resists degradation at temperatures of more than 140° F. to less than 0° F.
  • the hemostatic product should resist degradation when exposed to the elevated temperature such as up to about 150° F. for more than about 3 hours. In other embodiments, the hemostatic product should resist degradation when exposed to the elevated temperature for up to about 24 hours.
  • a threshold for the hemostatic product to be viewed as not experiencing degradation is that the hemostatic product does not exhibit noticeable visible physical changes when viewing the hemostatic product without magnification.
  • the hemostatic product should also not experience noticeable physical changes when the hemostatic product is examined with magnification such as with a magnifying glass or a microscope.
  • the preceding characteristics should be displayed by the hemostatic product regardless of whether the hemostatic product is retained in the packaging materials while exposed to the elevated temperature conditions.
  • the stabilizer also enhances the usable shelf life of the hemostatic product.
  • the stabilizer provides the hemostatic product with a shelf life of at least about 2 years.
  • the hemostatic product exhibits a shelf life of at least 3 years.
  • the term usable shelf life means that the hemostatic product does not exhibit noticeable degradation when viewed without magnification or with magnification such as a magnifying glass or microscope.
  • the hemostatic products also include one or more support structures or support materials incorporated therein.
  • a backing may be incorporated into the hemostatic product.
  • the support material may be formed from various electrospun materials such as polyglycolic acid (PGA), polylactic acid (PLA), and their copolymers (PLGAs); charged nylon, etc.
  • the support material is compressed electrospun dextran fibers.
  • compressed electrospun dextran fibers it is meant that electrospun dextran fibers are compressed together under pressure.
  • the support material may or may not be soluble in liquid, or may be slowly soluble in liquid, and may or may not be permeable to liquid.
  • Slowly soluble materials include those from which absorbable or dissolving (biodegradable) stitches or sutures are formed, included PGA, polylactic and caprolactone polymers.
  • the support material may dissolve relatively quickly such as less than about 1 hour. In other embodiments, the support material may dissolve within from about 10 days to 8 weeks. In either case, the support material provides the advantage of not having to remove the hemostatic product and risk disrupting the clot. [0081] However, in any case, the support material should not interfere with the immediate dissolution of the hemostatic product and delivery of the active agents associated therewith into the liquid that dissolves the hemostatic product.
  • the hemostatic product may be sterilized prior to use, generally by using electromagnetic radiation, for example, X-rays, gamma rays, ultraviolet light, etc.
  • electromagnetic radiation for example, X-rays, gamma rays, ultraviolet light, etc.
  • the hemostatic products are sterilized using X-rays in a dose of about 5 kilograys (kGray). Any method that does not destroy the carrier or the activity of substances associated with the fibers may be used to sterilize the hemostatic products of the invention.
  • the hemostatic product may also include diagnostic agents that can be used by the treating medical professional to diagnose the nature of the injury.
  • the diagnostic agent may change colors to indicate the presence of particular chemicals in the blood or to indicate particular characteristics of the blood. For example, if the patient is currently taking medications that cause thinning of the patient's blood.
  • the diagnostic agents could also change colors to indicate the oxygen and/or glucose level of the blood.
  • the products of the invention need not comprise agents that promote clotting.
  • the products of the invention are highly suitable for delivering many substances of interest to a desired liquid environment or location.
  • the products may be designed for delivery of therapeutic or beneficial substances to any moist environment of the body, where there is sufficient liquid to dissolve the electrospun dextran fibers and release the active substance, and where dissolved dextran is not problematic.
  • Such substances may include, for example, enzymes or their precursors (e.g. proenzymes or zymogens) and their substrates, substances that activate a protein or enzyme (e.g. proteases, cofactors, etc.), and the like.
  • hemostatic products comprised of only thrombin might be used for small injuries or in combination with other interventions.
  • other therapeutically beneficial substances may also be associated with the hemostatic product, including but not limited to: antibiotics, antiviral agents, anti-helminthic agents, anti-fungal agents, medicaments that alleviate pain, growth factors, bone morphogenic protein, vasoactive materials (e.g. substances that cause vasospasms), steroids to reduce inflammation, chemotherapy agents, contraceptives, etc.
  • Examples include but are not limited to oral, nasal, tracheal, anal, lung, and vaginal delivery of substances such as anti-microbial agents, analgesic agents, nutritional agents, etc.
  • Oral applications include the delivery of substances useful for dental treatments, e.g. antibiotics, pain medications, whitening agents, etc.
  • no bodily fluid is present (or if insufficient body fluid is present) and the applied hemostatic product can be "activated" by wetting, e.g. by spraying, or by otherwise applying a source of moisture (e.g. by exposing the hemostatic product to a moist material such as a sponge), or dropping hemostatic products into a liquid (e.g. a body of water), to cause release of the agents of interest associated with the dextran fibers.
  • a source of moisture e.g. by exposing the hemostatic product to a moist material such as a sponge
  • a liquid e.g. a body of water
  • the electrospun dextran fiber hemostatic products of the invention may serve as a
  • “scaffolding" or carrier for containing, storing and/or transporting the substance(s) until use, i.e. until contacted with liquid that dissolves the electrospun dextran fibers, concomitantly releasing the substances into the liquid.
  • substances may include, for example, enzymes or their precursors (e.g. pro-enzymes or zymogens) and their substrates, substances that activate a protein or enzyme (e.g. proteases, cofactors, etc.), and the like.
  • the pressure is provided by direct manual pressure such as using a human hand.
  • a material is placed over the wound and the direct manual pressure is used to hold the material in place.
  • the material may have absorbent capabilities such that blood and other fluids that are in proximity to the material are absorbed into the material. In such situations, it is possible for the clot to become associated with the material such as on the surface of the material or at least partially in the matrix of the material.
  • the concepts of the invention may be adapted for use in conjunction with other animals.
  • animals on which the invention can be used include dogs and cats.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé de formation d'un produit hémostatique. Une solution est formée avec un matériau polymère. Un système d'électrofilage est fourni, le système possédant une première buse et une seconde buse. La solution de matériau polymère est passée à travers la première buse et un agent hémostatique est passé à travers la seconde buse pour former une fibre électrofilée dans laquelle le matériau polymère recouvre au moins partiellement l'agent hémostatique. La fibre électrofilée est déposée sur un support pour former le produit hémostatique.
EP18819809.7A 2017-06-20 2018-06-20 Produits hémostatiques Withdrawn EP3641738A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762522288P 2017-06-20 2017-06-20
PCT/US2018/038542 WO2018237031A1 (fr) 2017-06-20 2018-06-20 Produits hémostatiques

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EP3641738A1 true EP3641738A1 (fr) 2020-04-29
EP3641738A4 EP3641738A4 (fr) 2021-04-21

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US (1) US20180361012A1 (fr)
EP (1) EP3641738A4 (fr)
AU (1) AU2018289509A1 (fr)
CA (1) CA3067583A1 (fr)
IL (1) IL271469A (fr)
WO (1) WO2018237031A1 (fr)

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KR101989054B1 (ko) * 2017-11-28 2019-06-13 (주)다림티센 지혈용 조성물 및 이를 포함하는 용기
CN115887736B (zh) * 2022-12-30 2024-07-19 青岛大学 不对称结构的止血纤维膜及其制备方法

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DE10204819A1 (de) * 2002-01-31 2003-08-14 Aesculap Ag & Co Kg Blutstillungsmittel und seine Bereitstellung für die Medizin
US8481074B2 (en) * 2004-07-16 2013-07-09 Poly-Med, Inc. Hemostatic microfibrous constructs
AU2006214371A1 (en) * 2005-02-15 2006-08-24 Virginia Commonwealth University Mineral technologies (MT) for acute hemostasis and for the treatment of acute wounds and chronic ulcers
AU2009234203B2 (en) * 2008-04-11 2014-06-12 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Electrospun dextran fibers and devices formed therefrom
US20100291182A1 (en) * 2009-01-21 2010-11-18 Arsenal Medical, Inc. Drug-Loaded Fibers
US20110111012A1 (en) * 2009-11-12 2011-05-12 Hemcon Medical Technologies, Inc. Nanomaterial wound dressing assembly
EP2768541A4 (fr) * 2011-10-18 2015-05-06 St Teresa Med Inc Procédé de formation de feuilles de dextran et de thrombine
US8697118B2 (en) * 2011-10-18 2014-04-15 St. Teresa Medical, Inc. Stabilizers for hemostatic products
CN103505758B (zh) * 2013-09-17 2015-02-11 南通南京大学材料工程技术研究院 壳聚糖纳米纤维止血材料及其制备方法
WO2015073539A1 (fr) * 2013-11-12 2015-05-21 St. Teresa Medical, Inc. Produits hémostatiques

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Publication number Publication date
AU2018289509A1 (en) 2020-01-16
WO2018237031A1 (fr) 2018-12-27
IL271469A (en) 2020-01-30
EP3641738A4 (fr) 2021-04-21
US20180361012A1 (en) 2018-12-20
CA3067583A1 (fr) 2018-12-27

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